Clinical significance and potential regulatory mechanism of overexpression of pituitary tumor-transforming gene transcription factor in bladder cancer

Background: Pituitary tumor transforming gene-1 (PTTG1) transcription factor is identified carcinogenic and associated with tumor invasiveness, but its roles in bladder cancer (BLCA) remains obscure. This research is intended to analyze the aberrant expression and clinical significance of PTTG1 in BLCA, to explore the relationship between PTTG1 and tumor microenvironment characteristics, and to predict its potential transcriptional activity in BLAC tissue. Methods: We compared the expression discrepancy of PTTG1 mRNA in BLCA and normal bladder tissue, using the BLCA transcriptomic datasets from GEO, ArrayExpress, TCGA, and GTEx. In-house immunohistochemical staining was implemented to determine the PTTG1 protein intensity. The prognostic value of PTTG1 was evaluated using the Kaplan-Meier Plotter. CRISPR screen data was utilized to estimate the effect PTTG1 interference has on BLCA cell lines. We predicted the immune cells abundance in BLCA tumor microenvironment using the microenvironment cell populations-counter and ESTIMATE algorithms. Single cell sequencing data was applied to identify the major cell types in BLCA cancer, and the dynamics of BLCA progression was revealed using pseudotime analysis. PTTG1 target genes were predicted by CistromeDB. Results: The elevated expression level of PTTG1 was confirmed in 1037 BLCA samples compared with 127 non-BLCA samples, with a standard mean difference value of 1.04. Higher PTTG1 expression status exhibited poorer BLCA prognosis. Moreover, the PTTG1 Chronos genetic effect scores were negative, indicating PTTG1 silence may inhibit the proliferation and survival of BLCA cells. With PTTG1 mRNA expression level increasing, higher natural killer, cytotoxic lymphocyte, and monocyte lineage cells infiltration levels were observed. A total of four candidate targets containing CHEK2 , OCIAD2 , UBE2L3 and ZNF367 were determined ultimately. Conclusions: PTTG1 mRNA over-expression may become a potential biomarker for BLCA prognosis. Additionally, PTTG1 may correlate with BLCA tumor microenvironment and exert transcriptional activity by targeting CHEK2 , OCIAD2 , UBE2L3 , and ZNF367 in BLCA tissue.